The gaseous mediators nitric oxide (NO) and carbon monoxide (CO) are widely implicated in the lung disease, and have been identified as candidate therapeutic targets and biomarkers of lung disease. Both NO and CO are endogenously produced in mammalian cells, including the epithelial cells lining the lung alveoli. As such, these mediators are well positioned to modulate lung epithelial cell function, including the regulation of alveolar fluid volume, which is undertaken by the concerted action of a series of ion channels, notably, the epithelial sodium channel (ENaC) as well as ion pumps, notably, the sodium/potassium ATPase (Na/K-ATPase). Our recent studies have addressed (i) what are the effects of the gaseous mediators NO and CO in alveolar ion and fluid transport, and (ii) by what mechanism do NO and CO impact alveolar ion transport. Endogenous NO is a key signalling molecule in the lung through the action of nitric oxide synthases on the amino acid arginine. The use of NO donors papaNONOate and deaNONOate demonstrated that NO can rapidly inhibit amiloride-sensitive short-circuit currents across polarised H441 cell monolayers as assessed by Ussing chamber studies. This phenomenon could be neutralised by NO scavengers, was independent of soluble guanylate cyclase signalling such as [1,2,4]oxadiazolo[4,3-]quinoxalin-1-one. Both the sodium channel and sodium pump components of the alveolar epithelial transport systems were targeted by NO. Permeabilisation of the basolateral membrane of H441 cell monolayers, it was evident that No targeted highly-selective, amiloride-sensitive Na+ channels in the apical membrane, although was without effect on human αβγENaC expressed in Xenopus oocytes, leading to speculation that NO may impact the cellular regulatory mechanisms of ENaC activity in H441 cells. In contrast, apical permeabilisation of H441 cell monolayers revealed that NO also targets the Na,K-ATPase on the basolateral membrane, where NO appeared to drive S-nitrosylation of the α subunit of the Na/K-ATPase in H441 cells, and hence, impair Na/K-ATPase function. Exogenous CO has been proposed as an inhalative treatment for lung disease, and has been explored – to date – primarily as an anti-inflammatory strategy in experimental animals models. Furthermore, endogenous CO, generated by the action of haemoxygenases, has been proposed as an endogenous modulator of alveolar ion transport. Interestingly, CO, when applied exogenously to isolated, ventilated, and perfused rabbit lungs has been demonstrated to impair alveolar sodium transport, and hence, impede the clearance of alveolar oedema fluid. These studies are supported by data from cell-culture studies, where exposure of polarised monolayers of bronchial epithelial cells or alveolar type II cells either to CO-donor molecules, or to CO gas directly, impairs the sodium transport capacity of the cell monolayer. This has been attributed to perturbed amiloride-sensitive ENaC activity, since CO was able to rapidly decrease the amiloride affinity of ENaC, without impacting (i) soluble guanylate cyclase/cyclic guanosine monophosphate signalling, (ii) ENaC trafficking, or (iii) Na/K-ATPase activity. The precise mechanism(s) by which CO inhibits ENaC activity remains unclear. These data support a role for NO and CO in regulating alveolar ion transport, and hence, lung fluid balance, and underscore the importance of gaseous mediators in regulation lung epithelial cell function. The ease of local administration of gaseous mediators to the lung underscores their potential usefulness as interventional agents in the management of lung disease.